ASYMMETRICAL CORTICAL DEGENERATIVE SYNDROMES
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1 ASYMMETRICAL CORTICAL DEGENERATIVE SYNDROMES Richard Caselli, MD Professor & Chair, Department of Neurology Mayo Clinic Arizona & Clinical Core Director, Arizona Alzheimer s Disease Center Objectives: Correlate symptom patterns with regional atrophy Distinguish dementia syndromes from causative diseases Understand the principles of treatment that underlie all neurodegenerative dementias. DISCLOSURE OF COMMERCIAL SUPPORT Richard Caselli, MD does not have a significant financial interest or other relationship with manufacturer(s) of commercial product(s) and /or provider(s) of commercial services discussed in this presentation 2009 All Rights Reserved 33
2 Slide 1 When It s Not Alzheimer s Disease Focal And Asymmetric Cortical Degeneration Syndromes Richard J. Caselli, MD Mayo Clinic Scottsdale, Arizona Slide 2 Terminology Dementia is the disabling impairment of multiple cognitive functions, it is not memory loss alone. Alzheimer s disease is the most common cause of dementia Each dementia syndrome has a distinctive cognitive/neurological profile that correlates imperfectly with histopathology Slide 3 Why Isolated Memory Loss Should Be Considered a Focal Neurological Sign 2009 All Rights Reserved 34
3 Slide 4 Dementia: Diagnostic Categories Alzheimer s Disease Alzheimer s Dementia Alzheimer Variants (e.g., Visual) Dementia and Parkinsonism Parkinson s Disease with dementia Dementia with Lewy Bodies Frontotemporal Dementia and Related Disorders Progressive Nonfluent Aphasia Semantic dementia Frontotemporal dementia FTD-ALS Vascular Dementia Slide 5 Neuropsychology of Dementia Test Alzheimer s Dementia Progressive Aphasia CBD FLD Amnesia Bitemporal Neuropsych WAIS-R VIQ normal moderate normal normal normal normal WAIS-R PIQ moderate normal severe mild normal normal Newlearning severe moderate normal moderate severe severe Recall severe moderate mild moderate severe severe Naming moderate moderate normal normal normal severe Comprehension mod-severe mod-severe normal mod-severe normal normal Psychomotor speed normal-mild severe severe severe normal mild Cognitive flexibility mild-mod normal-mild normal-mod severe normal mod-severe Constructional moderate normal severe normal-mod normal normal-mild praxis Anosogosia yes no no yes no Yes AVLT-trial 5 5/15 7/15 12/15 9/15 7/15 10/15 AVLT-STM 3/5 7/7 12/12 8/9 0/7 6/10 AVLT-LTM 1/5 5/7 12/12 9/9 0/7 4/10 WCST-perservative Nt 15 (mild) Nt 121 (severe) 10 (mild) 37 (mild-mod) CFT-copy 4 (<10%) 38 (100%) 17 (<10%) 34 (70%) 36 (100%) 34 (70%) CFT-recall 0 (<10%) 17 (20%) Nt 14(<10%) 3.5 (<10%) 15(10%) STMS 17/38 35/38 34/38 36/38 32/38 36/38 Slide 6 Case History: Visual Variant Alzheimer s Disease 59 yo man was getting lost on his motorcycle in familiar parts of town. Ophthalmologic examination was normal and visual field testing interpreted as psychogenic. Three years later he is unable to read or find light switches All Rights Reserved 35
4 Slide 7 Visual Variant Alzheimer s Disease Right > Left Occipitoparietal Atrophy Slide 8 Case History: Progressive Apraxia 60 yo airline pilot failed his recertification exam because of difficulty finding switches on the dashboard. He developed severe, progressive left greater than right arm apraxia over the next several years. His twin brother remains unaffected. Slide 9 Progressive Apraxia 2009 All Rights Reserved 36
5 Slide 10 Case History: Frontotemporal Degeneration An 62 yo retired marines officer and sharpshooter began following cars too closely, driving too slowly, veering out of his lane, and running stop signs. He maintained an arsenal of weapons at home, continued to be an excellent shot, and had an IQ of 120. His wife was angry because he 1) urinated in the backyard, 2) fed their dog when he was not supposed to, and 3) failed to water the plants. Slide 11 Frontotemporal Dementia Slide All Rights Reserved 37
6 Slide 13 MND and Aphasic Dementia Slide 14 Aphasia in a Patient with MND Slide 15 R>L Bitemporal Variant FTD: The Mean Marine 2009 All Rights Reserved 38
7 Slide 16 Case History: ProgressiveAphasia 72 yo woman drove unaccompanied from Arkansas to Minnesota in February, got stuck 6 times, obtained the assistance of truckers, and managed to return home after a week long evaluation. Good thing she didn t have to explain it to a policeman. Slide 17 Progressive Aphasia Slide 18 Semantic Dementia (Anomia): Right > Left Bitemporal Atrophy WAIS III VC 110 PO 114 WMI 119 PSI 111 AVLT LTM 89% BNT 56/60 Token 41/44 WCST 6 Categories 12 Perseverative Errors Judgment of Line Orientation 13/30 Facial Recognition Test 36 Famous Faces 3/ All Rights Reserved 39
8 Slide 19 FTD-like Tauopathy Bifrontal atrophy in PSP Slide 20 Parkinsonism and Dementia Parkinson s disease Dementia with Lewy Bodies Progressive Supranuclear Palsy Corticobasal Ganglionic Degeneration Tauopathy related FTD-PD Slide 21 Frequency of Dementia in Patients with Parkinson sdisease Prevalence estimates from clinical series range from 2% to over 77% (median 20-30%) Annual incidence ranges from 2.6% to 9.5% among PD patients initially nondemented, and increases with age Neuropath studies of PD brains show 32% neocortical LB s on H&E, but 76% with ubiquitin stains Concomitant AD changes in 50% of PD-dementia patients 2009 All Rights Reserved 40
9 Slide 22 Subcortical Dementia (PSP) Learning more impaired than recall Psychomotor slowing Relative preservation of naming Association with EPS and disease-specific features Slide 23 Dementia With Lewy Bodies: Four Cardinal Clinical Features Dementia Parkinsonism (levodopa responsive) Visual Hallucinations REM Behavior Disorder Slide 24 McKeith Criteria for DLB: Clinical Diagnosis Disabling cognitive decline (especially attention, frontalsubcortical skills, and visuospatial; memory later) Two of the following for probable; one for possible: fluctuating cognition (attention/alertness) visual hallucinations parkinsonism Supportive features: falls, syncope, neuroleptic sensitivity, delusions, other hallucinations Detractor features: stroke or other illness 2009 All Rights Reserved 41
10 Slide 25 McKeith Criteria for DLB: Neuropathologic Essential: Lewy bodies brainstem: substantia nigra, locus ceruleus, dorsal vagal nucleus cortex: frontal (areas 8,9), temporal (area 21), parietal (area 40) paralimbic: anterior cingulate, transentorhinal Supportive: LB-related neurites, amyloid plaques, NFT s, regional neuronal loss esp brainstem (SN, LC), and nbm, spongiform change, neurotransmitter deficits Slide 26 Dementia With Lewy Bodies: McKeith Criteria (1996) Dementia features attention visuospatial problem solving fluctuations Neuropathology with Alzheimer s disease without Alzheimer s disease Slide 27 Dementia With Lewy Bodies: A Nosological Challenge A 58 yo woman developed progressive speech and language problems clinically diagnosed as primary progressive aphasia. At age 64 she developed paranoid delusions and visual hallucinations. At age 65 parkinsonism started. She died at age All Rights Reserved 42
11 Slide 28 CHROMOSOME 17-RELATED DEMENTIAS Clinical Syndromes Neuropathology Authors Disinhibition- Dementia- Parkinsonism- Amyotrophy-Complex (DDPAC) Progressive subcortical gliosis Nonspecific Wilhelmsen 94; Lynch 94 Nonspecific, PrP Petersen 95 Progressive aphasia Neurofibrillary tangles Bird 97 PSP syndrome Fibrillary tau inclusions Ghetti 97; Farlow 97 Slide 29 Genetics of Familial Parkinson s Disease Gene Chromosome Inheritance Alpha-Synuclein 4 Auto Dominant Parkin 6 Auto Recessive UCH-L1 4 Auto Dominant PARK3 2 Auto Dominant PARK4 4 Auto Dominant PARK6 1 Auto Recessive PARK7 1 Auto Recessive SCA 2 14 Auto Dominant SCA 3 12 Auto Dominant *Identical twins concordance rate +/- 5% Slide 30 Treatment of the Patient with Dementia 1. Prevention 2. Intellectual Decline 3. Behavioral Disturbances 4. Sleep Disorders 5. Associated Problems 6. Abrupt Decline 2009 All Rights Reserved 43
12 Slide 31 Slide 32 Prevention 1. Positive clinical trials: Antioxidants (Vitamin E, CoQ10) 2. Negative clinical trials: prednisone, NSAIDs, estrogen, hydergine, gingko? 3. Ongoing clinical trials: folate, B6, B12; Statins Treatment of the Patient with Dementia: Intellectual Decline 1. Donepezil (Aricept) 2. Rivastigmine (Exelon) 3. Galantamine (Reminyl) 4. Tacrine (Cognex) Slide 33 Behavioral Disturbances 1. Psychosis and Agitation 2. Depression 3. Anxiety 2009 All Rights Reserved 44
13 Slide 34 Behavioral Disturbances 1. Psychosis and Agitation a. Atypical Antipsychotic Agents i. Quetiapine (Seroquel) ii. Olanzepine (Zyprexa) iii. Risperidone (Risperdal) b. Typical Antipsychotic Agents i. Haloperidol (Haldol) c. Environmental Adjustments Slide 35 Behavioral Disturbances 2. Depression a. SSRI s b. Trazadone c. Avoid TCA s Slide 36 Behavioral Disturbances 3. Anxiety a. Buspirone (Buspar) b. Neuroleptics c. Paradoxical Reactions (benzodiazepines) 2009 All Rights Reserved 45
14 Slide 37 Sleep Disorders 1. Insomnia a. Zolpidem (Ambien) b. Zaleplon (Sonata) c. Antihistamines 2. REM Behavior Disorder a. Clonazepam b. Melatonin 3. Restless Legs Syndrome a. Gabapentin (Neurontin) b. Carbidopa/levodopa (Sinemet) c. Clonazepam, narcotics, other Slide 38 Associated Problems 1. Parkinsonism 2. Incontinence 3. Dysphagia Slide 39 Abrupt Decline 1. Infections (UTI #1) 2. Medications 3. Pain 4. Other SystemicProcess 5. Neurologic Process 6. Post-op 2009 All Rights Reserved 46
15 Slide 40 Abrupt cognitive decline in a 64 year old man with DLBD 2009 All Rights Reserved 47
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